Cholecystokinin (CCK) is a neuropeptide with a widespread distribution in brain. CCK receptors are classified into two types; CCK.sub.A and CCK.sub.B, both of which are present in brain (Woodruff, G. N. and Hughes, J., 1991, Ann. Rev. Pharmacol. 31, 469-501).
CI-988, the chemical name is: [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1 .sup.3,7 ]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutano ic acid, and the structure is: ##STR1## It is a potent CCK.sub.B antagonist with high selectivity for CCK.sub.B receptors (Hughes, J., et al, 1990, Proc. Natl. Acad. Sci., USA, 87 6728-6732). CCK.sub.B antagonists have been shown to have anxiolytic-like activity in animal models of anxiety (Hughes, J., et al, Proc. Natl. Acad. Sci., USA, 87, 6728-6732; Singl, L., Lewis, A. S., Field, M. J., Hughes, J., and Woodruff, G. N., 1991, Proc. Natl. Acad. Sci., USA, 88, 1130-1133), suggesting a physiological role for CCK in anxiety. It has also been suggested that CCK may be involved in the control of food intake and in analgesic responses (Woodruff, G. N. and Hughes, J., 1991, Ann. Rev. Pharmacol. 31, 469-501).
CCK.sub.A antagonists include but are not limited to (1R-trans)-N-[.alpha.-methyl-N-[[(2-methylcyclohexyl)oxy]carbonyl]-L-trypt ophyl]-D-3-(phenylmethyl)((1R,2R)-N-[[(2-methylcyclohexyl)oxy]carbonyl])(.a lpha./-Me)LTrp-(D-3-Bzl)bAla-.beta.-alanine ((-)-isomer) and N-[.alpha.-methyl-N-[(tricyclo[3.3.1.1.sup.3,7 ]dec-2-yloxy)carbonyl]-L-tryptophyl]-D-3-(phenylmethyl)-.beta.-alanine.
Mixed CCK.sub.A and CCK.sub.B antagonists include but are not limited to (1S-trans)-N-[.alpha.-methyl-N-[[(2-methylcyclohexyl)oxy]carbonyl]-D-trypt ophyl]-L-3-(phenylmethyl)-.beta.-alanine.
The above CCK antagonists have been described in EPA 0405537. These antagonists are also described in U.S. application Ser. No. 07/629,809, filed Dec. 19, 1990, the disclosure of which is hereby incorporated by reference.
Other CCK an have been described in pending U.S. application Ser. Nos. 07/726,656, 07/726,655, 07/726,654, 07/726,653, 07/726,652, and 07/726,651 are filed on Jul. 12, 1991, the disclosures of which are also hereby incorporated by reference.
The above patents and applications cover the compounds of the instant invention, methods for preparing them, and several uses thereof.
The above references do not disclose the use of CCK.sub.B antagonists for treating depression.
Depression can be the result of organic disease, secondary to stress associated with personal loss, or idiopathic in origin. There is a strong tendency for familial occurrence of some forms of depression suggesting a mechanistic cause for at least some forms of depression. The diagnosis of depression is made primarily by quantification of alterations in patients' mood. These evaluations of mood are generally performed by a physician or quantified by a neuropsychologist using validated rating scales such as the Hamilton Depression Rating Scale or the Brief Psychiatric Rating Scale. Numerous other scales have been developed to quantify and measure the degree of mood alterations in patients with depression, such as insomnia, difficulty with concentration, lack of energy, feelings of worthlessness, and guilt. The standards for diagnosis of depression as well as all psychiatric diagnoses are collected in the diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) referred to as the DSM-III-R manual published by the American Psychiatric Association, 1987.
The compounds of the instant invention are indicated as having an antidepressant action in patients with major and minor forms of depression .